The class of mammalian biologically active polypeptides called growth factors influence the proliferation, differentiation, motility, maintenance and apoptosis of target cells. On-going studies in my laboratory are directed towards understanding the mechanism of action and biological role of growth factors which signal through the ErbB family of receptors . To address these issues, we utilize techniques common to protein biochemistry, cell biology and molecular biology. The ErbB family of receptors which include the epidermal growth factor receptor (EGFR), ErbB2, ErbB3 and ErbB4 mediate the biological actions of a family of growth factors which are structurally related to EGF. Members of this family of mitogens such as EGF and amphiregulin require the presence of the EGFR on cells for signaling, whereas signal transduction by the heregulins (HRGs; neu differentiation factor, neuregulin, acetylcholine receptor-inducing activity, glial growth factor) is initiated via an interaction with either ErbB3 or ErbB4. It is known that the catalytic activity of the Src homology 2 (SH2) domain-containing protein-tyrosine phosphatase SHP-2 is requisite for EGF-stimulated mitogen-activated protein kinase (MAPK; extracellular signal-regulated kinase) activation and cell cycle progression. In this report we studied the functional role of SHP-2 in ErbB family-mediated activation of MAPK by overexpressing various SHP-2 mutants in Cos-7 cells. Our results demonstrate that the enzymatic activity and both the NH2- and COOH-terminal SH2 domains of SHP-2 are required for EGF-induced MAPK stimulation, whereas these SHP-2 structures were not essential for the activation of MAPK which occurred in response to myristoylated Son of sevenless, activated Ras or phorbol ester. In striking contrast to MAPK activation, SHP-2 was found to play no role in the activation of c-Jun amino-terminal kinase (JNK) which occurred in response to EGF. Ectopic expression of either ErbB3 or ErbB4 in Cos-7 cells reconstituted both HRG a- or HRG b-stimulated MAPK activation and this activation was blocked by the same mutant SHP-2 structures that inhibited the EGF-induced stimulation of MAPK. These results demonstrate that SHP-2 performs a common and essential function(s) in ligand-stimulated activation of MAPK by the ErbB family of receptors.